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Antimicrobial Agents and Chemotherapy, April 2003, p. 1241-1250, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1241-1250.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Single Nucleotide Polymorphisms in Genes Associated with Isoniazid Resistance in Mycobacterium tuberculosis

Srinivas V. Ramaswamy,1 Robert Reich,1 Shu-Jun Dou,1 Linda Jasperse,1 Xi Pan,1 Audrey Wanger,2 Teresa Quitugua,3 and Edward A. Graviss1*

Houston Tuberculosis Initiative, Department of Pathology, Baylor College of Medicine,1 Department of Pathology, University of Texas Medical School, Houston, Texas 77030,2 Department of Microbiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 782453

Received 9 April 2002/ Returned for modification 4 June 2002/ Accepted 10 December 2002

Isoniazid (INH) is a central component of drug regimens used worldwide to treat tuberculosis. Previous studies have identified resistance-associated mutations in katG, inhA, kasA, ndh, and the oxyR-ahpC intergenic region. DNA microarray-based experiments have shown that INH induces several genes in Mycobacterium tuberculosis that encode proteins physiologically relevant to the drug's mode of action. To gain further insight into the molecular genetic basis of INH resistance, 20 genes implicated in INH resistance were sequenced for INH resistance-associated mutations. Thirty-eight INH-monoresistant clinical isolates and 86 INH-susceptible isolates of M. tuberculosis were obtained from the Texas Department of Health and the Houston Tuberculosis Initiative. Epidemiologic independence was established for all isolates by IS6110 restriction fragment length polymorphism analysis. Susceptible isolates were matched with resistant isolates by molecular genetic group and IS6110 profiles. Spoligotyping was done with isolates with five or fewer IS6110 copies. A major genetic group was established on the basis of the polymorphisms in katG codon 463 and gyrA codon 95. MICs were determined by the E-test. Semiquantitative catalase assays were performed with isolates with mutations in the katG gene. When the 20 genes were sequenced, it was found that 17 (44.7%) INH-resistant isolates had a single-locus, resistance-associated mutation in the katG, mabA, or Rv1772 gene. Seventeen (44.7%) INH-resistant isolates had resistance-associated mutations in two or more genes, and 76% of all INH-resistant isolates had a mutation in the katG gene. Mutations were also identified in the fadE24, Rv1592c, Rv1772, Rv0340, and iniBAC genes, recently shown by DNA-based microarray experiments to be upregulated in response to INH. In general, the MICs were higher for isolates with mutations in katG and the isolates had reduced catalase activities. The results show that a variety of single nucleotide polymorphisms in multiple genes are found exclusively in INH-resistant clinical isolates. These genes either are involved in mycolic acid biosynthesis or are overexpressed as a response to the buildup or cellular toxicity of INH.

* Corresponding author. Mailing address: Houston Tuberculosis Initiative, Department of Pathology (209E), Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Phone: (713) 798-8022. Fax: (713) 798-8895. E-mail: egraviss{at}bcm.tmc.edu.

Antimicrobial Agents and Chemotherapy, April 2003, p. 1241-1250, Vol. 47, No. 4
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.4.1241-1250.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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